Current therapies for autoimmune diseases target the symptoms rather than the cause of autoimmunity. The chronic use of immunosuppressants leads to deliberating side effects. An attractive alternative is to treat the underlying cause by boosting regulatory T cells (Tregs) in patients with autoimmunity. Our group established that IL-2 is an essential cytokine for Tregs. Moreover, we have established in pre-clinical studies that low IL-2R signaling promotes Tregs but not T effector/memory (TEM) cells. This finding has led to the notion that low-dose (LD) IL-2 may selectively expand Tregs. Importantly, LD IL-2 therapy has shown promising results in patients with chronic GvHD, HCV vasculitis, and several autoimmune diseases. Correspondingly, several fundamental questions emerge about LD IL-2 immunotherapy. These include: What is the selectivity of LD IL-2 for Tregs? What is the mechanism by which Tregs preferentially respond to low levels of IL-2? Is there individual variation in responsiveness to LD IL-2? What are the molecular consequences in Treg and Teff cells in response to LD IL-2? Does chronic exposure to LD IL-2 alter the capacity of Tregs to respond to IL-2? Our supporting data has defined a window of selectivity of human Tregs for IL-2R signaling when compared to CD45RO CD4 TEM ++ cells. However, the extent that Tregs exclusive respond to LD IL-2 remains a point of contention. We also have preliminary data that IL-2-dependent gene activation in Tregs may vary in normal subjects. This latter point is of interest because some individuals may be more suitable candidates for this therapy. We plan to build on these results and capitalize on our expertise on IL-2 to better understand mechanistically the potential of LD IL- 2 as a treatment platform for autoimmune diseases. The premise of this application is: In comparison to TEM cells, low levels of IL-2R signaling selectively and substantially activates an IL-2-dependent transcriptional program in Tregs that is uniquely shaped by TCR and co-stimulatory signaling; this selective gene activation varies between individuals and accounts for variable responses to LD IL-2 therapy. The following specific aims are proposed to address this premise: 1) To establish the immediate and down-stream consequences of IL-2R signaling by LD IL-2 on gene regulation in human Treg and Teff cells in vitro alone or in the context of TCR and co-stimulatory signaling; 2) to evaluate cellular and molecular levels through which the response by human Tregs varies to LD IL-2 in normal subjects and in patients with Type 1 diabetes; and 3) to evaluate the consequence of IL-2 in Treg and TEM cells in patients undergoing LD IL-2 therapy. These experiments will assess the outcome of IL-2R signaling due to variation of IL-2 dose and the type of autoimmune disease.